The preparation and use of ortho-sulfonamido arylhydroxamic acids as matrix metalloproteinase inhibitors

ABSTRACT

Ortho-sulfonamido aryl hydroxamic acids are provided which are useful, inter alia, for the inhibition of matrix metalloproteinases and the treatment of conditions associated with overexpression of MMPs.

BACKGROUND OF THE INVENTION

[0001] The present invention relates to novel, low molecular weight,non-peptide inhibitors of matrix metalloproteinases (e.g. gelatinases,stromelysins and collagenases) which are useful for the treatment ofdiseases in which these enzymes are implicated such as arthritis, tumormetastasis, tissue ulceration, abnormal wound healing, periodontaldisease, bone disease, proteinuria, aneurysmal aortic disease,degenerative cartilage loss following traumatic joint injury,demyelinating diseases of the nervous system and HIV infection.

[0002] More particularly this invention provides orthosulfonamido arylhydroxamine acids as matrix metalloproteinase inhibitors processes fortheir preparation and pharmaceutical compositions containing them.

[0003] Matrix metalloproteinases (MMPs) are a group of enzymes that havebeen implicated in the pathological destruction of connective tissue andbasement membranes [Woessner, J. F., Jr. FASEB J. 1991, 5, 2145;Birkedal-Hansen, H.; Moore, W. G. I.; Bodden, M. K.; Windsor, L. J.;Birkedal-Hansen, B.; DeCarlo, A.; Engler, J. A. Crit. Rev. Oral Biol.Med. 1993, 4, 197; Cawston, T. E. Pharmacol. Ther. 1996, 70, 163;Powell, W. C.; Matrisian, L. M. Cur. Top. Microbiol. and Immunol. 1996,213, 1]. These zinc containing endopeptidases consist of several subsetsof enzymes including collagenases, stromelysins and gelatinases. Ofthese classes, the gelatinases have been shown to be the MMPs mostintimately involved with the growth and spread of tumors, while thecollagenases have been associated with the pathogenesis ofosteoarthritis [Howell, D. S.; Pelletier, J.-P. In Arthritis and AlliedConditions; McCarthy, D. J.; Koopman, W. J., Eds.; Lea and Febiger:Philadelphia, 1993; 12th Edition Vol. 2, pp. 1723; Dean, D. D. Sem.Arthritis Rheum. 1991, 20, 2; Crawford, H. C; Matrisian, L. M. InvasionMetast. 1994-95, 14, 234; Ray, J. M.; Stetler-Stevenson, W. G. Exp.Opin. Invest. Drugs, 1996, 5, 323].

[0004] It is known that the level of expression of gelatinase iselevated in malignancies, and that gelatinase can degrade the basementmembrane which may lead to tumor metastasis [Powell, W. C.; Matrisian,L. M. Cur. Top. Microbiol. and Immunol. 1996, 213, 1; Crawford, H. C;Matrisian, L. M. Invasion Metast. 1994-95, 14, 234; Ray, J. M.;Stetler-Stevenson, W. G. Exp. Opin. Invest. Drugs, 1996, 5, 323;Himelstein, B. P.; Canete-Soler, R.; Bernhard, E. J.; Dilks, D. W.;Muschel, R. J. Invasion Metast. 1994-95, 14, 246; Nuovo, G. J.;MacConnell, P. B.; Simsir, A.; Valea, F.; French, D. L. Cancer Res.1995, 55, 267-275; Walther, M. M.; Levy, A.; Hurley, K.; Venzon, D.;Linehen, W. M.; Stetler-Stevenson, W. J. Urol. 1995, 153 (Suppl. 4),403A; Tokuraku, M; Sato, H.; Murakami, S.; Okada, Y.; Watanabe, Y.;Seiki, M. Int. J. Cancer, 1995, 64, 355; Himelstein, B.; Hua, J.;Bernhard, E.; Muschel, R. J. Proc. Am. Assoc. Cancer Res. Ann. Meet.1996, 37, 632; Ueda, Y.; Imai, K.; Tsuchiya, H.; Fujimoto, N.;Nakanishi, I.; Katsuda, S.; Seiki, M.; Okada, Y. Am. J. Pathol. 1996,148, 611; Gress, T.M.; Mueller-Pillasch, F.; Lerch, M. M.; Friess, H.;Buechler, M.; Adler, G. Int. J. Cancer, 1995, 62, 407; Kawashima, A.;Nakanishi, I.; Tsuchiya, H.; Roessner, A.; Obata, K.; Okada, Y. VirchowsArch., 1994, 424, 547-552.]. Angiogenesis, required for the growth ofsolid tumors, has also recently been shown to have a gelatinasecomponent to its pathology [Crawford, H. C; Matrisian, L. M. InvasionMetast. 1994-95, 14, 234; Ray, J. M.; Stetler-Stevenson, W. G. Exp.Opin. Invest. Drugs, 1996, 5, 323.]. Furthermore, there is evidence tosuggest that gelatinase is involved in plaque rupture associated withatherosclerosis [Dollery, C. M.; McEwan, J. R.; Henney, A. M. Circ. Res.1995, 77, 863; Zempo, N.; Koyama, N.; Kenagy, R. D.; Lea, H.J.; Clowes,A. W. Arterioscler. Thromb. Vasc. Biol. 1996, 16, 28; Lee, R. T.;Schoen, F. J.; Loree, H. M.; Lark, M. W., Libby, P. Arterioscler.Thromb. Vasc. Biol. 1996, 16, 1070.]. Other conditions mediated by MMPsare restenosis, MMP-mediated osteopenias, inflammatory diseases of thecentral nervous system, skin aging, tumor growth, osteoarthritis,rheumatoid arthritis, septic arthritis, corneal ulceration, abnormalwound healing, bone disease, proteinuria, aneurysmal aortic disease,degenerative cartilage loss following traumatic joint injury,demyelinating diseases of the nervous system, cirrhosis of the liver,glomerular disease of the kidney, premature rupture of fetal membranes,inflammatory bowel disease, periodontal disease, age related maculardegeneration, diabetic retinopathy, proliferative vitreoretinopathy,retinopathy of prematurity, ocular inflammation, keratoconus, Sjogren'ssyndrome, myopia, ocular tumors, ocular angiogenesis/neovascularizationand corneal graft rejection.

[0005] The hypothesis that MMPs are important mediators of the tissuedestruction that occurs in arthritis has long been considered, since itwas first recognized that these enzymes are capable of degradingcollagens and proteoglycans which are the major structural components ofcartilage [Sapolsky, A. I.; Keiser, H.; Howell, D. S.; Woessner, J. F.,Jr.; J. Clin. Invest. 1976, 58, 1030; Pelletier, J.-P.;Martel-Pelletier, J.; Howell, D. S.; Ghandur-Mnaymneh, L.; Enis, J. E.;Woessner, J. F., Jr., Arthritis Rheum. 1983, 26, 63.], and continues todevelop as new MMPs are identified. For example, collagenase-3 (MMP-13)was cloned from breast cancer cells in 1994, and the first report thatit could be involved in arthritis appeared in 1995 [Freiji, J. M.;Diez-Itza, I.; Balbin, M.; Sanchez, L. M.; Blasco, R.; Tolivia, J.;Lopez-Otin, C. J. Biol. Chem. 1994, 269, 16766; Flannery, C. R.; Sandy,J. D. 102-17, 41st Ann. Meet. Orth. Res. Soc. Orlando, Fla. Feb. 13-16,1995.]. Evidence is accumulating that implicates MMP-13 in thepathogenesis of arthritis. A major structural component of articularcartilage, type II collagen, is the preferred substrate for MMP-13 andthis enzyme is significantly more efficient at cleaving type II collagenthan the other collagenases [Knauper, V.; Lopez-Otin, C.; Smith, B.;Knight, G.; Murphy, G. J. Biol. Chem., 1996, 271, 1544-1550; Mitchell,P. G.; Magna, H. A.; Reeves, L. M.; Lopresti-Morrow, L. L.; Yocum, S.A.; Rosner, P. J.; Geoghegan, K. F.; Hambor, J. E. J. Clin. Invest.1996, 97, 761.]. MMP-13 is produced by chondrocytes, and elevated levelsof MMP-13 has been found in human osteoarthritic tissues [Reboul, P.;Pelletier, J-P.; Hambor, J.; Magna, H.; Tardif, G.; Cloutier, J-M.;Martel-Pelletier, J. Arthritis Rheum. 1995, 38 (SuppL 9), S268; Shlopov,B. V.; Mainardi, C. L.; Hasty, K. A. Arthritis Rheum. 1995, 38 (Suppl.9), S313; Reboul, P.; Pelletier, J-P.; Tardif, G.; Cloutier, J-M.;Martel-Pelletier, J. J. Clin. Invest. 1996, 97, 2011]. Potent inhibitorsof MMPs were described over 10 years ago, but the poor bioavailabilityof these early peptidic, substrate mimetic MMP inhibitors precludedtheir evaluation in animal models of arthritis. More bioavailable,non-peptidic MMP inhibitors may be preferred for the treatment ofdiseases mediated by MMPs.

[0006] It is expected that small molecule inhibitors of gelatinasetherefore have the potential for treating a variety of disease states.While a variety of MMP inhibitors have been identified and disclosed inthe literature, the vast majority of these molecules are peptidic orpeptide-like compounds that may have bioavailability and pharmacokineticproblems that would limit their clinical effectiveness. Low molecularweight, potent, long-acting, orally bioavailable inhibitors ofgelatinases and collagenases are therefore highly desirable for thepotential chronic treatment of the above mentioned disease states.Several non-peptidc, sulfur-containing hydroxamic acids have recentlybeen disclosed and are listed below.

[0007] U.S. Pat. Nos. 5,455,258, 5,506,242 and 5,552,419, as well asEuropean patent application EP606,046A1 and WIPO internationalpublications WO96/00214 and WO97/22587 disclose non-peptide matrixmetalloproteinase inhibitors of which the compound CGS27023A isrepresentative. The discovery of this type of MMP inhibitor is furtherdetailed by MacPherson, et. al. in J. Med. Chem., (1997),40, 2525.Additional publications disclosing sulfonamide based MMP inhibitorswhich are variants of the sulfonamide-hydroxamate shown below, or theanalogous sulfonamide-carboxylates, are European patent applicationEP-757984-A1 and WIPO international publications WO95/35275, WO95/35276,WO96/27583, WO97/19068 and WO97/27174.

[0008] Publications disclosing β-sulfonamide-hydroxamate MMP inhibitoranalogs of CGS 27023A in which the carbon alpha to the hydroxamic acidhas been joined in a ring to the sulfonamide nitrogen, as shown below,include WIPO international publications WO96/33 172 and WO97/20824.

[0009] The German patent application DE19,542,189-A1 disclosesadditional examples of cylic sulfonamides as MMP inhibitors. In thiscase the sulfonamide-containing ring is fused to a phenyl ring to forman isoquinoline.

[0010] Analogs of the sulfonamide-hydroxamate MMP inhibitors in whichthe sulfonamide nitrogen has been replaced by a carbon atom, as shown inthe general structure below, are European patent applicationEP-780386-A1 and WIPO international publication WO97/24117.

[0011] Certain ortho-sulfonamido aryl hydroxamic acids are described inU.S. Pat. No. 5,929,097, WO9816514 and WO9816520.

DESCRIPTION OF THE INVENTION

[0012] The MMP inhibiting ortho-sulfonamido aryl hydroxamic acids of thepresent invention are represented by formula I

[0013] where the hydroxamic acid moiety and the sulfonamido moiety arebonded to adjacent carbons of group A where:

[0014] A is aryl, heteroaryl or heteroaryl fused to a phenyl ring;

[0015] Z is aryl, heteroaryl, or heteroaryl fused to a phenyl;

[0016] E and G are independently CH₂, NR⁵, or O, or S or a bond:

[0017] Y is cycloalkyl, cycloheteroalkyl, —C₁-C₅-perfluoroalkyl, alkyl,alkenyl, alkynyl, heteroalkyl, alkylaryl, or heteroaryl;

[0018] J is aryl, heteroaryl, heteroaryl fused to a phenyl, cycloalkyl,cycloheteroalkyl, —C₁-C₅-perfluoroalkyl, alkyl, alkenyl, or alkynyl;

[0019] R⁵ and R⁶ are independently H, aryl, heteroaryl, cycloalkyl,cycloheteroalkyl, —C₁-C₄-perfluoroalkyl, alkyl, alkenyl, or alkynyl;

[0020] R⁷ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,cycloalkyl or 3-6 membered cycloheteroalkyl; or

[0021] R⁷CH₂—N-A- can form a non-aromatic 1,2-benzo-fused 7-10 memberedheterocyclic ring optionally containing an additional heteroatomselected from O, S and N wherein said heterocyclic ring may beoptionally fused to another benzene ring;

[0022] L is —C(O)—, S(O)_(y), —NR⁵C(O)NR⁶—, —NR⁵C(O)O—, —OC(O)NR⁵—,—SC(O)—, —C(O)S—, —NR⁵C(O)—, —C(O)NR⁵—, —SC(O)NR⁵, —NR⁵C(O)S—, —OC(O)O—;

[0023] y is 1 or 2;

[0024] and the pharmaceutically acceptable salts thereof and the opticalisomers and diastereomers thereof.

[0025] Preferred compounds of the invention are those wherein:

[0026] A is aryl, heteroaryl or heteroaryl fused to a phenyl ringoptionally substituted by one or more of R¹, R², R³ and R⁴ the same ordifferent;

[0027] Z is aryl, heteroaryl, or heteroaryl fused to a phenyl,optionally substituted by one or more of R¹⁰, R¹¹, R¹²and R¹³ the sameor different;

[0028] R¹, R², R³, R⁴, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R²⁰, R²¹,R²², R²³ R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R³⁰ and R³¹ are independently —H,—COR⁵, —F, —Br, —Cl, —I, C(O)NR⁵OR⁶, —CN, —OR⁵, —C₁-C₄-perfluoroalkyl,—S(O)_(x)R⁵, —OPO(OR⁵)OR⁶, —PO(OR⁶)R⁵, —OC(O)NR⁵R⁶, —COOR⁵, —CONR⁵R⁶,—SO₃H, —NR⁵R⁶, —NR⁵COR⁶, —NR⁵COOR⁶, —SO₂NR⁵R⁶, —NO₂, —N(R⁵)SO₂R⁶,NR⁵CONR⁵R⁶NR⁵C(═NR⁶)NR⁵R⁶, 3-6 membered cycloheteroalkyl, aryl,heteroaryl, biphenyl, —SO₂NHCOR¹⁸, —CONHSO₂R¹⁸, -tetrazol-5-yl,—SO₂NHCN, —SO₂NHCONR⁵R⁶ or straight chain or branched —C₁-C₆ alkyl,—C₂-C₆-alkenyl, or —C₂-C₆-alkynyl, or —C₃-C₆-cycloalkyl, each optionallysubstituted with —COR⁵, —CN, —C₂-C₆ alkenyl, —C₂-C₆ alkynyl, —OR⁵,—C₁-C₄-perfluoroalkyl, —S(O)_(x)R⁵, —OC(O)NR⁵R⁶, —COOR⁵, —CONR⁵R⁶,—SO₃H, —NR⁵R⁶, —NR⁵COR⁶, —NR⁵COOR⁶, —SO₂NR⁵R⁶, —NO₂, —N(R⁵)SO₂R⁶,—NR⁵CONR⁵R⁶, —C₃-C₆cycloalkyl, 3-6 membered cycloheteroalkyl, aryl,heteroaryl, biphenyl, —SO₂NHCOR¹⁸, —CONHSO₂R¹⁸; —PO(OR⁵)OR⁶, —PO(OR⁶)R⁵,-tetrazol-5-yl, C(O)NR⁵OR⁶, —NR⁵C(═NR⁶)NR⁵R⁶, —SO₂NHCONR⁵R⁶ or —SO₂NHCN;or

[0029] when any of R¹ and R², or R10 and R¹¹ or R¹⁴ and R¹⁵ are onadjacent carbons of A or J or Z respectively, then each pair of R¹ andR², or R¹⁰ and R¹¹ or R¹⁴ and R¹⁵ together with the carbons to whichthey are attached can form a 5 to 7 membered saturated or unsaturatedheterocyclic ring, a 5-6 membered heteroaryl ring, or a 5 to 7 memberedsaturated or unsaturated carbocyclic ring;

[0030] x is 0-2;

[0031] E and G are independently CH₂, NR⁵, or O, or S or a bond:

[0032] Y is —C₃-C₆-cycloalkyl, —C₃-C₆-cycloheteroalkyl,—C₁-C₅-perfluoroalkyl, straight chain or branched —C₁-C₆ alkyl, straightor branched chain —C₂-C₆-alkenyl, or straight or branched chainC₂-C₆-alkynyl or heteroalkyl alkylaryl, heteroaryl optionallysubstituted with R²⁰, R²¹, R²², and R²³;

[0033] J is aryl, heteroaryl, or heteroaryl fused to a phenyl;optionally substituted with R¹⁴, R¹⁵, R¹⁶, and R¹⁷ or —C₃-C₆-cycloalkyl,—C₃-C₆-cycloheteroalkyl —C₁-C₅-perfluoroalkyl, straight chain orbranched —C₁-C₆ alkyl, straight or branched chain —C₂-C₆-alkenyl, orstraight or branched chain C₂-C₆-alkynyl;

[0034] R⁵ and R⁶ are independently H, aryl, heteroaryl,—C₃-C₆-cycloalkyl, —C₃-C₆-cycloheteroalkyl, —C₁-C₄-perfluoroalkyl, orstraight chain or branched —C₁-C₆ alkyl, —C₂-C₆-alkenyl, or—C₂-C₆-alkynyl, each optionally substituted with —OH, —COR⁸, —CN,—C(O)NR⁸OR⁹, —C₂-C₆-alkenyl, —C₂-C₆-alkynyl, —OR⁸,—C₁-C₄-perfluoroalkyl, —S(O)_(x)R⁸, —OPO(OR⁸)OR⁹, —PO(OR⁸)R⁹,—OC(O)NR⁸R⁹, —COOR⁸, —CONR⁸R⁹, —SO₃H, —NR⁸R⁹, —NCOR⁸R⁹, —NR⁸COOR⁹,—SO₂NR⁸R⁹, —NO₂, —N(R⁸)SO₂R⁹, —NR⁸CONR⁸R⁹, —C₃-C₆ cycloalkyl, 3-6membered cycloheteroalkyl, aryl, heteroaryl, —SO₂NHCOR¹⁹, —CONHSO₂R¹⁹,-tetrazol-5-yl, NR⁸C(═NR⁹)NR⁸R⁹, —SO₂NHCONR⁸R⁹, or —SO₂NHCN;

[0035] R⁷ is hydrogen, straight chain or branched —C₁-C₆-alkyl,—C₂-C₆-alkenyl, or —C₂-C₆-alkynyl each optionally substituted with —OH,—COR⁵, —CN, —C₂-C₆-alkenyl, —C₂-C₆-alkynyl, —OR⁵, —C₁-C₄-perfluoroalkyl,—S(O)_(x)R⁵, OPO(OR⁵)OR⁶, —PO(OR⁵)R⁶, —OC(O)NR⁵R⁶, —COOR⁵, —CONR⁵R⁶,—SO₃H, —NR⁵R⁶, —NR⁵COR⁶, —NR⁵COOR⁶, —SO₂NR⁵R⁶, —NO₂, —N(R⁵)SO₂R⁶,—NR⁵CONR⁵R⁶, —C₃-C₆ cycloalkyl, —C₃-C₆-cycloheteroalkyl, -aryl,heteroaryl, —SO₂NHCOR³², —CONHSO₂R³², -tetrazol-5-yl, —NR⁵C(═NR⁶)NR⁵R⁶,—C(O)NR⁵OR⁶, —SO₂NHCONR⁵R⁶ or —SO₂NHCN;

[0036] or R⁷ is phenyl or naphthyl, optionally substituted by R²⁴, R²⁵,R²⁶ and R²⁷ or a 5 to 6 membered heteroaryl group optionally substitutedby R²⁸, R²⁹, R³⁰ and R³¹; or

[0037] R⁷ is C₃-C₆ cycloalkyl or 3-6 membered cycloheteroalkyl; orR⁷CH₂—N—A- (where R⁷ is bonded to A) can form a non-aromatic1,2-benzo-fused 7-10 membered heterocyclic ring optionally containing anadditional heteroatom selected from O, S and N wherein said heterocyclicring may be optionally fused to another benzene ring such as forexample:

[0038] or (fused):

[0039] R⁸ and R⁹ are independently H, aryl or heteroaryl, —C₃-C₇cycloalkyl or 3 to 6 membered cycloheteroalkyl, —C₁-C₄-perfluoroalkyl,straight chain or branched —C₁-C₆-alkyl, —C₂-C₆-alkenyl, or—C₂-C₆-alkynyl, each optionally substituted with hydroxy, alkoxy,aryloxy, —C₁-C₄-perfluoroalkyl, amino, mono- and di-C₁-C₆-alkylamino,carboxylic acid, carboalkoxy and carboaryloxy, nitro, cyano, carboxamidoprimary, mono- and di-C₁-C₆-alkylcarbamoyl;

[0040] R¹⁸ and R³² are independently aryl, heteroaryl,—C₃-C₆-cycloalkyl, —C₃-C₆-cycloheteroalkyl, —C₁-C₄-perfluoroalkyl, orstraight chain or branched —C₁-C₆ alkyl, —C₂-C₆-alkenyl, or—C₂-C₆-alkynyl, each optionally substituted with —OH, —COR⁸, —CN,—C(O)NR⁸OR⁹, —C₂-C₆-alkenyl, —C₂-C₆-alkynyl, —OR⁸,—C₁-C₄-perfluoroalkyl, —S(O)_(x)R⁸, —OPO(OR⁸)OR⁹, —PO(OR⁸)R⁹,—OC(O)NR⁸R⁹, —COOR⁸, —CONR⁸R⁹, —SO₃H, —NR⁸R⁹, —NCOR⁸R⁹, —NR⁸COOR⁹,—SO₂NR⁸R⁹, —NO₂, —N(R⁸)SO₂R⁹, —NR⁸CONR⁸R⁹, —C₃-C₆ cycloalkyl, 3-6membered cycloheteroalkyl, aryl, heteroaryl, —SO₂NHCOR19, —CONHSO₂R¹⁹,-tetrazol-5-yl, NR⁸C(═NR⁹)NR⁸R⁹, —SO₂NHCONR⁸R⁹, or —SO₂NHCN;

[0041] R¹⁹ is aryl or heteroaryl, —C₃-C₇cycloalkyl or 3 to 6 memberedcycloheteroalkyl, —C₁-C₄-perfluoroalkyl, straight chain or branched—C₁-C₆-alkyl, —C₂-C₆-alkenyl, or —C₂-C₆-alkynyl, each optionallysubstituted with hydroxy, alkoxy, aryloxy, —C₁-C₄-perfluoroalkyl, amino,mono- and di-C₁-C₆-alkylamino, carboxylic acid, carboalkoxy andcarboaryloxy, nitro, cyano, carboxamido primary, mono- anddi-C₁-C₆-alkylcarbamoyl;

[0042] L is —C(O)—, S(O)_(y), —NR⁵C(O)NR⁶—, —NR⁵C(O)O—, —OC(O)NR⁵—,—SC(O)—, —C(O)S—, —NR⁵C(O)—, —C(O)NR⁵—, —SC(O)NR⁵, —NR⁵C(O)S—, —OC(O)O—;

[0043] y is 1 or 2;

[0044] and the pharmaceutically acceptable salts thereof and the opticalisomers and diastereomers thereof.

[0045] It is preferred in some embodiments of the invention that both ofthe carbons of A adjacent to the carbon bearing the sulfonamido grouphave a substituent other than hydrogen.

[0046] Examples of A are phenyl optionally substituted by C₁-C₆ straightor branched chain alkyl.

[0047] Examples of Z are phenyl, e.g. where E ispara to the —SO2— group.

[0048] In accordance with some preferred embodiments of the presentinvention, E and G are independently selected from NH, O and S. In otherpreferred embodiments of the present invention E is O and G is NH.

[0049] In other preferred embodiments Y is C₁-C₆ straight chain alkyl,and more preferably C₂-C₃ straight chain alkyl.

[0050] In some embodiments of the present invention E and G areindependently selected from CH₂, NH, O and S and Y is—C₁-C₄-perfluoroalkyl, or straight chain or branched —C₁-C₆ alkyl,—C₂-C₆-alkenyl, or C₂-C₆-alkynyl.

[0051] In still other embodiments of the present invention, E and G areindependently selected from CH₂, NH, O and S and Y is straight chain orbranched —C₁-C₆ alkyl.

[0052] When G is CH₂, in some embodiments of the invention, it ispreferred that Y is —C₂-C₅-perfluoroalkyl, or straight chain or branched—C₁-C₆ alkyl,

[0053] In still other embodiments of the present invention, E and G areCH₂, and Y is straight chain or branched —C₁-C₆ alkyl, and morepreferably Y is straight chain or branched —C₁-C₅ alkyl.

[0054] J is preferably heteroaryl fused to a phenyl and particularlypreferred is where J is benzofuranyl, benzothienyl and quinolinyl. J maybe indolyl.

[0055] When R¹⁴ and R¹⁵ are on adjacent atoms of J, R¹⁴, R¹⁵ and J maytogether preferably form a bicyclic oxygen containing aryl moiety suchas benzodioxanyl or benzodioxlyl.

[0056] Preferred compounds of the present invention include:

[0057] Quinoline-2-carboxylic acid(2-{4-[(2-hydroxycarbamoyl-6-methyl-phenyl)-methyl-sulfamoyl]-phenoxy}-ethyl)-amide

[0058] Benzofuran-2-carboxylic acid(3-{4-[(2-hydroxycarbamoyl-6-methyl-phenyl)-methyl-sulfamoyl]-phenoxy}-propyl)-amide

[0059] Benzofuran-2-carboxylic acid(4-{4-[(2-hydroxycarbamoyl-6-methyl-phenyl)-methyl-sulfamoyl]-phenoxy}-butyl)-amide

[0060] 1H-Indole-2-carboxylic acid(3-{4-[(2-hydroxycarbamoyl-6-methyl-phenyl)-methyl-sulfamoyl]-phenoxy}-propyl)-amide

[0061] Benzo[b]thiophene-2-carboxylic acid(2-{4-[(2-hydroxycarbamoyl-6-methyl-phenyl)-methyl-sulfamoyl]-phenoxy}-ethyl)-amide

[0062] N-{3-[4-({2-[(Hydroxyamino)carbonyl]-6-dimethylanilino}sulfonyl)-phenoxy]propyl}-1,3-benzodioxole-5-carboxamide

[0063] N-{4-[4-({2-[(Hydroxyamino)carbonyl]-6-dimethylanilino}sulfonyl)-phenoxy]butyl}-1,3-benzodioxole-5-carboxamide

[0064]N-{3-[4-({2-[(Hydroxyamino)carbonyl]-6-dimethylanilino}-sulfonyl)-phenoxy]propyl}-1-benzothiophene-2-carboxamide

[0065] Benzofuran-2-carboxylic acid(2-{4-[benzyl-(2-hydroxycarbamoyl-4,6-dimethyl-phenyl)-sulfamoyl]-phenoxy}-ethyl)-amide.

[0066] Halogen, as used herein means fluoro, chloro, bromo and iodo.

[0067] Alkyl as used herein means a branched or straight chain radicalhaving from 1 to 20 carbon atoms optionally substituted with one or moregroups selected from halogen, cyano, nitro, hydroxy, sulfhydryl, amino,alkylamino, dialkylamino, alkoxy, aryloxy, thioalkyl, thioaryl, acyl,aroyl, acyloxy, acylamino, carboxy, carboxyalkyl, carboxyaryl,carboxamido, carboxamidoalkyl, carboxamidodialkyl, alkylsulfonamido,arylsulfonamido, aryl, heteroaryl, and more preferably from 1 to 6carbon atoms also optionally substituted. Exemplary alkyl groups includebut are not limited to methyl, ethyl, propyl, isopropyl, butyl,isobutyl, t-butyl, pentyl and hexyl also optionally substituted as wellas perfluoroalkyl.

[0068] Alkenyl as used herein means a branched or straight chain radicalhaving from 2 to 20 carbon atoms optionally substituted with one or moregroups selected from halogen, cyano, nitro, hydroxy, sulfhydryl, amino,alkylamino, dialkylamino, alkoxy, aryloxy, thioalkyl, thioaryl, acyl,aroyl, acyloxy, acylamino, carboxy, carboxyalkyl, carboxyaryl,carboxamido, carboxamidoalkyl, carboxamidodialkyl, alkylsulfonamido,arylsulfonamido, aryl, heteroaryl, and more preferably from 2 to 6carbon atoms, with the chain containing at least one carbon-carbondouble bond. Alkenyl, may be used synonymously with the term olefin andincludes alkylidenes. Exemplary alkenyl groups include but are notlimited to ethylene, propylene and isobutylene.

[0069] Alkynyl as used herein means a branched or straight chain radicalhaving from 2 to 20 carbon atoms optionally substituted with one or moregroups selected from halogen, cyano, nitro, hydroxy, sulfhydryl, amino,alkylamino, dialkylamino, alkoxy, aryloxy, thioalkyl, thioaryl, acyl,aroyl, acyloxy, acylamino, carboxy, carboxyalkyl, carboxyaryl,carboxamido, carboxamidoalkyl, carboxamidodialkyl, alkylsulfonamido,arylsulfonamido, aryl, heteroaryl, and more preferably from 3 to 10carbon atoms, with the chain containing at least one carbon-carbontriple bond.

[0070] Alkoxy as used herein means an alkyl-O— group in which the alkylgroup is as previously described. Exemplary alkoxy groups include butare not limited to methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, andt-butoxy.

[0071] Aryl as used herein refers to phenyl or naphthyl which may beoptionally substituted as described above (e.g. R¹⁻⁴, R¹⁰⁻¹³, R¹⁴⁻¹⁷etc.,) such as with one to four substituents selected from the group ofalkyl, halogen, cyano, nitro, hydroxy, sulfhydryl, amino, alkylamino,dialkylamino, alkoxy, aryloxy, thioalkyl, thioaryl, acyl, aroyl,acyloxy, acylamino, carboxy, carboxyalkyl, carboxyaryl, carboxamido,carboxamidoalkyl, carboxamidodialkyl, alkylsulfonamido, arylsulfonamido,aryl, or heteroaryl.

[0072] Heteroaryl, as used herein refers to a 5-6 memberedheteroaromatic ring having from 1 to 3 heteroatoms independentlyselected from N, NH, O and S. Heteroaryl may be optionally substitutedwith substituents as described above (e.g. R¹⁻⁴, R¹⁰⁻¹³, R¹⁴⁻¹⁷) such asselected from the group halogen, cyano, nitro, hydroxy, sulfhydryl,amino, alkylamino, dialkylamino, alkoxy, aryloxy, thioalkyl, thioaryl,acyl, aroyl, acyloxy, acylamino, carboxy, carboxyalkyl, carboxyaryl,carboxamido, carboxamidoalkyl, carboxamidodialkyl, alkylsulfonamido,arylsulfonamido, aryl, and heteroaryl. Heteroaryl includes, but is notlimited to pyrrole, furan, thiophene, pyridine, pyrimidine, pyridazine,pyrazine, triazole, pyrazole, imidazole, isothiazole, thiazole,isoxazole and oxazole.

[0073] Cycloalkyl or saturated or unsaturated carbocyclic ring, refersto a cyclic alkyl group having from 3 to 7 carbon atoms and may includefrom 1 to 2 double bonds. Cycloalkyl groups may be optionallysubstituted.

[0074] Cycloheteroalkyl, as used herein refers to 3 to 7 memberedsaturated or unsaturated heterocyclic ring having one to threeheteroatoms independently selected from N, NH, O, and S and optionallyhaving 1 or 2 double bonds. Cycloheteroalkyl groups may be optionallysubstituted with from one to three groups. The term heterocycloalkyl orheterocyclic ring includes, but is not limited to oxazolidine,thiazolidine, imidazolidine, tetrahydrofuran, tetrahydrothiophene,tetramethylene sulfone, dihydropyran, tetrahydropyran, piperidine,pyrrolidine, dioxane, morpholine, azepine and diazepine.

[0075] The term “heteroaryl fused to a phenyl” includes, but is notlimited to, benzoxazole, benzoisoxazole, indole, isoindole,benzothiophene, benzofuran, quinoline, quinazoline, quinoxaline,benzotriazole, benzimidazole, benzthiazole, benzopyrazole andisoquinoline. Substitutions may occur on one or both rings.

[0076] Pharmaceutical acceptable salts are encompassed by the presentinvention and include, as appropriate, inorganic and organic salts.Exemplary acid salts include, but are not limited to acetate, adipate,alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate,butyrate, camphorate, camphorsulfonate, digluconate,cyclopentanepropionate, dodecylsulfate, ethanesulfonate,glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate,fumarate, hydrochloride, hydrobromide, hydroiodide,2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate,nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate,persulfate, 3-phenylpropionate, picrate, pivalate, propionate,succinate, tartrate, thiocyanate, tosylate, mesylate and undecanoate.

[0077] Other compounds that are acids can also form salts with alkalimetals or alkali earth metals, such as sodium, potassium, calcium, ormagnesium, or with organic bases or basic quaternary ammonium salts.

[0078] The compounds according to the invention can be in variousstereoisomeric forms such as enantiomers or diastereomers. The inventionincludes optically pure forms of compounds of the present inventionprepared in accordance with known methods.

[0079] The following compounds (1-10) which may be used in preparinginvention compounds are known and references are given hereinbelow.

[0080] Compound 1:

[0081] a) Meyer, Michael D.; Altenbach, Robert J.; Basha, Fatima Z.;Carroll, William A.; Drizin, Irene; Elmore, Steven W.; Kerwin, Jr JamesF.; Lebold, Suzanne A.; Lee, Edmund L.; Sippy, Kevin B.; Tietje, KarinR.; Wendt, Michael D. Tricyclic substituted hexahydrobenz[e]isoindolealpha-1 adrenergic antagonists. U.S. Pat. No. 5,597,823. CAN 126:199575.

[0082] b) Meyer, Michael D.; Altenbach, Robert J.; Basha, Fatima Z.;Carroll, William A.; Drizin, Irene; Kerwin, James F., Jr.; Lebold,Suzanne A.; Lee, Edmund L.; Elmore, Steven W.; et al. Preparation oftricyclic substituted benz[e]isoindoles as al adrenergic antagonists.PCT Int. Appl WO 9622992 Al CAN 125:221858.

[0083] Compound 2:

[0084] Troll, Theodor; Schmid, Klaus. Preparation and reactions of a2H-pyrrolo[3,4-b]pyridine and a 2H-pyrrolo[3,4-b]pyrazine. J.Heterocycl. Chem. (1986), 23(6), 1641-4.

[0085] Compound 3:

[0086] Meyer, Michael D.; Altenbach, Robert J.; Basha, Fatima Z.;Carroll, William A.; Drizin, Irene; Elmore, Steven W.; Kerwin, Jr JamesF.; Lebold, Suzanne A.; Lee, Edmund L.; Sippy, Kevin B.; Tietje, KarinR.; Wendt, Michael D. Tricyclic substituted hexahydrobenz[e]isoindolealpha-1 adrenergic antagonists. U.S. Pat. No. 5,597,823. CAN 126:199575.

[0087] Compound 4:

[0088] a) Meyer, Michael D.; Altenbach, Robert J.; Basha, Fatima Z.;Carroll, William A.; Drizin, Irene; Elmore, Steven W.; Kerwin, Jr JamesF.; Lebold, Suzanne A.; Lee, Edmund L.; Sippy, Kevin B.; Tietje, KarinR.; Wendt, Michael D. Tricyclic substituted hexahydrobenz[e]isoindolealpha-1 adrenergic antagonists. U.S. Pat. No. 5,597,823. CAN 126:199575.

[0089] b) Meyer, Michael D.; Altenbach, Robert J.; Basha, Fatima Z.;Carroll, William A.; Drizin, Irene; Kerwin, James F., Jr.; Lebold,Suzanne A.; Lee, Edmund L.; Elmore, Steven W.; et al. Preparation oftricyclic substituted benz[e]isoindoles as al adrenergic antagonists.PCT Int. Appl. WO 9622992 A1 CAN 125:221858.

[0090] Compound 5:

[0091] Geach, Neil; Hawkins, David William; Pearson, Christopher John;Smith, Philip Henry Gaunt; White, Nicolas. Preparation of isoxazoles asherbicides. Eur. Pat. Appl. EP 636622 A1 CAN 122:290845.

[0092] Compound 6:

[0093] Kotovskaya, S. K.; Mokrushina, G. A.; Suetina, T. A.; Chupakhin,O. N.; Zinchenko, E. Ya.; Lesovaya, Z. I.; Mezentsev, A. S.; Chernyshov,A. I.; Samoilova, L. N. Benzimidazolyl derivatives of penicillin andcephalosporin: synthesis and antimicrobial activity. Khim.-Farm. Zh.(1989), 23(8), 952-6.

[0094] Compound 7:

[0095] Wagner, Klaus. Bactericidal and fungicidal4-chlorobenzothiazoles. Ger. Offen. DE 2136924 CAN 78:111293.

[0096] Compound 8:

[0097] Eggensperger, Heinz; Diehl, Karl H.; Kloss, Wilfried.2-Hydroxy-4-alkoxybenzophenones. Ger. DE 1768599 711223. CAN 76:85557.

[0098] Compound 9:

[0099] Lichtenthaler, Frieder W.; Moser, Alfred. Nucleosides. 44.Benzo-separated pyrazolopyrimidines: expeditious syntheses of [3,4-g]-and [3,4-h]-linked pyrazoloquinazolinones. Tetrahedron Lett. (1981),22(44), 4397-400.

[0100] Compound 10:

[0101] Terpstra, Jan W.; Van Leusen, Albert M. A new synthesis ofbenzo[b]thiophenes and benzo[c]thiophenes by annulation of disubstitutedthiophenes. J. Org. Chem. (1986), 51(2), 230-8.

[0102] The invention compounds may be prepared using conventionaltechniques known to those skilled in the art of organic synthesis.

[0103] Accordingly this invention provides a process for preparing acompound of Formula I as defined above which comprises one of thefollowing:

[0104] a) reacting a compound of formula II:

[0105] wherein J, L, G, Y, E, Z, A and R⁷ are defined above or areactive derivative thereof, with a compound of formula III:

NH₂OH  (III)

[0106] to give a corresponding compound of formula I;

[0107] b) resolving a mixture (e.g. racemate) of optically activeisomers of a compound of formula I to isolate one enantiomer ordiastereomer substantially free of the other enantiomer ordiastereomers;

[0108] c) acidifying a basic compound of formula I with apharmaceutically acceptable acid to give a pharmaceutically acceptablesalt.

[0109] Means of coupling the carboxylic acid moiety to hydroxylamine arewell known to those skilled in the art.

[0110] The following schemes (Scheme I and II) illustrates the generalreaction sequence employed. For purposes of illustration only, whereinthe group A is a phenyl, methyl anthranilate is reacted withp-fluorobenzenesulfonyl chloride to provide the requisite N-arylsulfonamido-ester which is then alkylated to provide theN,N-disubstituted sulfonamide. This compound can then be converted intothe elongated sulfonamide by two routes. The N,N-disubstitutedsulfonamide ester may be hydrolyzed to the carboxylic acid and thensubjected to a nucleophilic displacement of the fluoro substituent, orit can be treated directly with a suitable nucleophile and subsequentlyhydrolyzed to the acid. The acid may then be converted into thecorresponding hydroxamic acid.

[0111] Scheme II depicts the preparation of suitable nucleophiles (forwhen E and G are independently N, O, or S and L is —C(O)— or S(O)x)employed in the displacement of the aryl fluoride.

[0112] Alternatively, other nucleophiles for use in the displacementreaction (G is C) can be prepared via the route in Scheme III. Asuitable ester is condensed with a lactone to provide a β-ketolactone.This lactone is then ring opened with concomitant decarboxylation toprovide the requisite nucleophile for use in the displacement reaction.

[0113] Alternatively, other compounds of the invention can be preparedvia the route shown in Scheme 4. For purposes of illustration only,wherein the group A is shown as a phenyl, methyl anthranilate is reactedwith p-bromobenzenesulfonyl chloride to provide the requisite N-arylsulfonamido-ester which is then alkylated to provide theN,N-disubstituted sulfonamide. This compound can then be converted intothe elongated sulfonamide by two routes. The N,N-disubstitutedsulfonamide ester may be hydrolyzed to the carboxylic acid and thensubjected to a palladium catalyzed coupling to a suitable alkyl boronreagent (compound A, prepared via the route depicted in Scheme 5), or itcan be treated directly with a suitable alkyl boron reagent andsubsequently hydrolyzed to the acid. The acid may then be converted intothe corresponding hydroxamic acid.

[0114] Compound A (where L is —C(O)—) may be prepared via the followingroute. A precursor carboxylic acid is converted to the Weinreb amide viaformation of the acid chloride and subsequent displacement withmethoxymethyl amine. The amide is then treated with a grignard reagent,the olefin of which is subsequently hydroborated with 9-BBN for use inthe palladium coupling reaction.

[0115] In another aspect of the present invention, the inventionincludes a method of treating a pathological condition or disordermediated by matrix metalloproteinases in mammals which comprisesproviding to a mammal in need thereof a therapeutically effective amountof a matrix metalloproteinase inhibiting compound

[0116] In preferred embodiments of the invention, compounds of thepresent invention are particularly useful for the treatment ofrheumatoid arthritis, tumor metastasis, tissue ulceration, abnormalwound healing, periodontal disease, bone disease and HIV infection.

[0117] Compounds of this invention may be provided to a patient in needthereof. They may be administered neat or with a pharmaceutical carrierto the patient or provided in the form of a pro-drug which will beconverted by the patient. The pharmaceutical carrier may be solid orliquid and generally may be any pharmaceutically acceptable carrier.Formulation of drugs is discussed, for example, in Hoover, J. E.,Remington 's Pharameutical Sciences, Mack Publishing Company, Easton,Pa., 1975.

[0118] Applicable solid carriers can include one or more substanceswhich may also act as flavoring agents, lubricants, solubilizers,suspending agents, fillers, glidants, compression aids, binders ortablet-disintegrating agents or an encapsulating material. In powders,the carrier is a finely divided solid which is in admixture with thefinely divided active ingredient. In tablets, the active ingredient ismixed with a carrier having the necessary compression properties insuitable proportions and compacted in the shape and size desired. Thepowders and tablets preferably contain up to 99% of the activeingredient. Suitable solid carriers include, for example, calciumphosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch,gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose,polyvinylpyrrolidine, low melting waxes and ion exchange resins.

[0119] Liquid carriers may be used in preparing solutions, suspensions,emulsions, syrups and elixirs. The active ingredient of this inventioncan be dissolved or suspended in a pharmaceutically acceptable liquidcarrier such as water, an organic solvent, a mixture of both orpharmaceutically acceptable oils or fat. The liquid carrier can containother suitable pharmaceutical additives such a solubilizers,emulsifiers, buffers, preservatives, sweeteners, flavoring agents,suspending agents, thickening agents, colors, viscosity regulators,stabilizers or osmo-regulators. Suitable examples of liquid carriers fororal and parenteral administration include water (particularlycontaining additives as above, e.g., cellulose derivatives, preferablesodium carboxymethyl cellulose solution), alcohols (including monohydricalcohols and polyhydric alcohols, e.g., glycols) and their derivatives,and oils (e.g., fractionated coconut oil and arachis oil). Forparenteral administration the carrier can also be an oily ester such asethyl oleate and isopropyl myristate. Sterile liquid carriers are usedin sterile liquid form compositions for parenteral administration.

[0120] Liquid pharmaceutical compositions which are sterile solutions orsuspensions can be utilized by, for example, intramuscular,intraperitoneal or subcutaneous injection. Sterile solutions can also beadministered intravenously. Oral administration may be either liquid orsolid composition form.

[0121] The compounds of this invention may be administered rectally inthe form of a conventional suppository. For administration by intranasalor intrabronchial inhalation or insufflation, the compounds of thisinvention may be formulated into an aqueous or partially aqueoussolution, which can then be utilized in the form of an aerosol. Thecompounds of this invention may also be administered transdermallythrough the use of a transdermal patch containing the active compoundand a carrier that is inert to the active compound, is non-toxic to theskin, and allows delivery of the agent for systemic absorption into theblood stream via the skin. The carrier may take any number of forms suchas creams and ointments, pastes, gels, and occlusive devices. The creamsand ointments may be viscous liquid or semi-solid emulsions of eitherthe oil in water or water in oil type. Pastes comprised of absorptivepowders dispersed in petroleum or hydrophilic petroleum containing theactive ingredient may also be suitable. A variety of occlusive devicesmay be used to release the active ingredient into the blood stream suchas a semipermeable membrane covering a reservoir containing the activeingredient with or without a carrier, or a matrix containing the activeingredient. Other occlusive devices are known in the literature.

[0122] The dosage to be used in the treatment of a specific patientsuffering from a disease or condition in which MMPs and TACE areinvolved must be subjectively determined by the attending physician. Thevariables involved include the severity of the dysfunction, and thesize, age, and response pattern of the patient. Treatment will generallybe initiated with small dosages less than the optimum dose of thecompound. Thereafter the dosage is increased until the optimum effectunder the circumstances is reached. Precise dosages for oral,parenteral, nasal, or intrabronchial administration will be determinedby the administering physician based on experience with the individualsubject treated and standard medical principles.

[0123] Preferably the pharmaceutical composition is in unit dosage form,e.g., as tablets or capsules. In such form, the composition issub-divided in unit dose containing appropriate quantities of the activeingredient; the unit dosage form can be packaged compositions, forexample packed powders, vials, ampoules, prefilled syringes or sachetscontaining liquids. The unit dosage form can be, for example, a capsuleor tablet itself, or it can be the appropriate number of any suchcompositions in package form.

[0124] The following specific examples are included for illustrativepurposes and are not to be construed as limiting to this disclosure inany way. Other procedures useful for the preparation of the compounds ofthis invention will be apparent to those skilled in the art of syntheticorganic chemistry.

EXAMPLE 1 Methyl 2-[[(4-fluorophenyl)sulfonyl](methyl)amino]3-methylBenzoate

[0125] Methyl 2-[[(4-fluorophenyl)sulfonyl]amino] 3-methyl benzoate (3.0g, 9.3 mmol) was dissolved in dimethylformamide (DMF) (30 ml) and cooledto 0° C. Iodomethane (0.75 ml, 12.0 mmol) was added, followed by sodiumhydride (0.4 g, 11 mmol, 60% dispersion in mineral oil) and the reactionwas allowed to warm to room temperature. After 15 hours, the reactionwas diluted with water and extracted 3 times with ethyl acetate. Theorganics were combined, washed with brine, dried over MgSO₄, andconcentrated in vacuo to provide 2.8 g (90%) of the N-methyl sulfonamideas a white solid. ¹H NMR (DMSO-d₆): δ 2.0 (s, CH3), 3.25 (s, CH3), 3.55(s, CH3), 7.1-7.57 (m, 5 Ar H), 7.69-7.73 (m, 2 Ar H). Electrospray MassSpec: m/z 338.3 (M+H)⁺.

EXAMPLE 2 Methyl 2-[[(4-fluorophenyl)sulfonyl](methyl)amino] 3-methylBenzoic Acid

[0126] The product of Example 1 (2.8 g, 8.3 mmol) and 0.4 g lithiumhydroxide (LiOH) were added to 65 ml of a (1:1.5:1) mixture oftetrahydrofuran (THF): methanol (MeOH): water, and stirred at roomtemperature. After 15 hours, the solution was neutralized with 1N HCland extracted 3 times with dichloromethane (CH₂Cl₂). The organics werecombined, washed with brine, dried over MgSO₄, and concentrated in vacuoto provide 2.56 g (95%) of the carboxylic acid as a white solid.

[0127]¹H NMR (DMSO-d₆): δ 1.9 (s, CH3), 3.20 (s, CH3), 7.35-7.46 (m, 4Ar H) 7.55-7.58 (d, 1 Ar H), 7.69-7.74 (m, 2 Ar H). Electrospray MassSpec: m/z 322.2 (M−H)⁺.

EXAMPLE 3 3-Methyl-2-[methyl[(4-[2-[(2-quinolyncarbonyl)amino]ethoxy]phenyl]sulfonyl]amino] Benzoic Acid

[0128] Sodium hydride (0.1 g, 2.3 mmol, 60% dispersion in mineral oil)was added to DMF (5 ml) and stirred at room temperature 10 minutes. Asolution of N-(2-hydroxyethyl) 2-quinolinecarboxamide (0.21 g, 0.99mmol) in DMF (1 ml) was added followed by a solution of the product ofExample 2 (0.3 g, 0.98 mmol) in DMF (1 ml). After 3 hours, the solutionwas diluted with ethyl acetate and a sticky solid was filtered off. Thesolid was taken up in water, and the solution was acidified with 1N HCl.Filtration of the resulting precipitate gave 0.29 g (49% yield) of whitepowder. ¹H NMR (DMSO-d₆): δ 1.9 (s, CH3), 3.17 (s, CH3), 3.75 (m, CH2),4.23 (m, CH2), 7.1 (d, 2 Ar H) 7.29-7.30 (m, 2 Ar H), 7.52-7.58 (m, 2 ArH), 7.71-7.76 (t, 1 Ar H), 7.86-7.91 (t, 1 Ar H), 8.0-8.2 (m, 3 Ar H),8.57-8.60 (d, 1 Ar H), 8.9 (s, 1 Ar H) 9.1 (br t, NH), 12.9 (s, OH).Electrospray Mass Spec: m/z 520.2 (M+H)⁺.

EXAMPLE 4 Quinoline-2-carboxylic acid(2-{4-[(2-hydroxycarbamoyl-6-methyl-phenyl)-methyl-sulfamoyl]-phenoxy}-ethyl)-amide

[0129] The product of Example 3 (0.17 g, 0.33 mmol) was dissolved in DMF(5 ml). 1-hydroxybenzotriazole (HOBT) (0.1 g, 0.8 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.17 g,0.92 mmol), hydroxylamine hydrochloride (0.18 g, 2.64 mmol) and finallytriethylamine (0.46 ml, 3.3 mmol) were added sequentially to thesolution and allowed to stir at room temperature. After 15 hours, ethylacetate was added and the resulting precipitate filtered and trituratedfrom ethyl ether to give 0.99 g (36% yield) of the hydroxamic acid as awhite powder. MP 114-121° C.; ¹H NMR (DMSO-d₆): δ 2.1 (s, CH3), 3.14 (s,CH3), 3.62 (m, CH2), 3.8 (m, CH2), 7.1 (d, 2 Ar H) 7.29-7.30 (m, 2 ArH), 7.52-7.58 (d, 1 Ar H), 7.71-7.76 (m, 3 Ar H), 7.86-7.91 (t, 1 Ar H),8.0-8.2 (m, 3 Ar H), 8.57-8.60 (d, 1 Ar H), 8.89 (s, NH) 9.1 (br t, NH),11.0 (s, OH). Electrospray Mass Spec: m/z 535.2 (M+H)⁺.

EXAMPLE 52-[(4-{3-[(Benzofuran-2-carbonyl)-amino]-propoxy}-benzenesulfonyl)-methyl-amino]-3-methyl-benzoicAcid

[0130] The product of Example 2 (0.442 g, 1.37 mmol) was coupled toN-(3-hydroxypropyl)-1-benzofuran-2-carboxamide (0.3 g, 1.37 mmol) usingthe procedure of Example 3 to provide 0.37 g (53% yield) of an off whitepowder. MP 184-186° C.;

[0131]¹H NMR (DMSO-d₆): δ 1.9 (s, CH3), 2.04 (t, CH2), 3.16 (s, CH3),3.46 (q, CH2), 4.0 (t, CH2), 7.01 (d, 2 Ar H) 7.30-7.78 (m, 10 Ar H),8.56 (t, NH), 12.4 (br s, OH). Electrospray Mass Spec: m/z 523.2 (M+H)⁺.

EXAMPLE 6 Benzofuran-2-carboxylic Acid(3-{4-[(2-hydroxycarbamoyl-6-methyl-phenyl)-methyl-sulfamoyl]-phenoxy}-propyl)-amide

[0132] The product of Example 5 (0.172 g, 0.33 mmol) was converted tothe hydroxamic acid using the procedure of Example 4 to provide 0.073 g(41% yield) of a white solid. MP 148-150° C.; ¹H NMR (DMSO-d₆): δ 2.1(s, CH3), 2.04 (t, CH2), 3.06 (s, CH3), 3.39 (q, CH2), 4.0 (t, CH2),7.01 (d, 2 Ar H) 7.30-7.78 (m, 10 Ar H), 8.85 (t, NH), 8.89 (s, NH),11.0 (s, OH). Electrospray Mass Spec: 538.1 m/z (M+H)⁺.

EXAMPLE 72-[(4-{4-[(Benzofuran-2-carbonyl)-amino]-butoxy}-benzenesulfonyl)-methyl-amino]-3-methyl-benzoicAcid

[0133] The product of Example 2 (0.40 g, 1.24 mmol) was coupled toN-(4-hydroxybutyl)-1-benzofuran-2-carboxamide, prepared according toExample 17, (0.29 g, 1.24 mmol) using the procedure of Example 3 toprovide 0.34 g (51% yield) of an off white powder. MP>200° C.; ¹H NMR(DMSO-d₆): δ 1.35-1.62 (m, CH2, CH2), 1.9 (s, CH3), 3.20 (s, CH3),3.32-3.41 (m, CH2, CH2), 7.0-7.1 (m, 4 Ar H), 7.35 (t, 1 Ar H), 7.45 (t,1 Ar H), 7.54 (s, 1 Ar H), 7.65 (d, 1 Ar H), 7.77 (d, 1 Ar H), 7.92 (m,3 Ar H) 8.8 (t, NH). Electrospray Mass Spec: m/z 537.2 (M+H)⁺.

EXAMPLE 8 Benzofuran-2-carboxylic Acid(4-{4-[(2-hydroxycarbamoyl-6-methyl-phenyl)-methyl-sulfamoyl]-phenoxy}-butyl)-amide

[0134] The product of Example 7 (0.2 g, 0.37 mmol) was converted to thehydroxamic acid using the procedure of Example 4 to provide 0.063 g (31%yield) of a white solid. MP 131-134° C.; ¹HNMR (DMSO-d₆): δ 1.7-1.8 (m,CH2, CH2), 1.9 (s, CH3), 3.20 (s, CH3), 3.34-3.41 (m, CH2, CH2), 7.0-7.1(d, 1 Ar H), 7.19 (d, 1 Ar H), 7.30-7.78 (m, 9 Ar H), 7.9 (d, 1 Ar H),8.79 (t, NH), 8.88 (br s, NH), 10.99 (s, OH). Electrospray Mass Spec:552.2 m/z (M+H)⁺.

EXAMPLE 92-[(4-{3-[(1H-Indole-2-carbonyl)-amino]-propoxy}-benzenesulfonyl)-methyl-amino]-3-methyl-benzoicAcid

[0135] The product of Example 2 (0.27 g, 0.83 mmol) was coupled toN-(3-hydroxypropyl)-1H-indole-2-carboxamide, prepared according toExample 18, (0.20 g, 0.91 mmol) using the procedure of Example 3 toprovide 0.4 g (91% yield) of yellow solid powder. MP 199° C.; ¹H NMR(DMSO-d₆): δ 1.9 (s, CH3), 2.0-2.1 (m, CH2), 3.20 (s, CH3), 3.32-3.51(m, CH2, CH2), 6.8-7.2 (m, 8 Ar H), 7.36 (d, 1 Ar H), 7.58 (d, 1 Ar H),7.78 (d, 1 Ar H), 7.93 (s, 1 NH), 8.52 (s, NH), 12.0 (s, OH).Electrospray Mass Spec: m/z 522.2 (M+H)⁺.

EXAMPLE 10 1H-Indole-2-carboxylic Acid(3-{4-[(2-hydroxycarbamoyl-6-methyl-phenyl)-methyl-sulfamoyl]-phenoxy}-propyl)-amide

[0136] The product of Example 9 (0.2 g, 0.38 mmol) was converted to thehydroxamic acid using the procedure of Example 4 to provide 0.112 g (55%yield) of a white solid. MP 144-146° C.; ¹H NMR (DMSO-d₆): δ 1.9 (s,CH3), 1.35-1.62 (m, CH2), 3.20 (s, CH3), 3.46-3.51 (m, CH2, CH2),7.0-7.19 (m, 5 Ar H), 7.28-7.40 (m, 3 Ar H), 7.43-7.55 (m, 2 Ar H), 7.7(d, 2 Ar H), 8.58 (t, NH), 8.9 (br s, NH), 10.9 (s, NH), 11.7 (s, OH).Electrospray Mass Spec: m/z 537.1 (M+H)⁺.

EXAMPLE 112-[(4-{3-[(Benzo[b]thiophene-2-carbonyl)-amino]-ethoxy}-benzenesulfonyl)-benzenesulfonyl)-methyl-amino]-3-methyl-benzoicAcid

[0137] The product of Example 2 (0.15 g, 0.846 mmol) was coupled toN-(2-hydroxyethyl)-1-benzothiophene-2-carboxamide, prepared according toExample 19, (0.11 g, 0.51 mmol) using the procedure of Example 3 toprovide 0.26 g (80% yield) of yellow solid. MP 250° C.; ¹H NMR(DMSO-d₆): δ 1.9 (s, CH3), 3.20 (s, CH3), 3.6 (m, CH2), 4.1 (m, CH2),7.0-7.17 (m, 4 Ar H), 7.34-7.37 (m, 2 Ar H), 7.81-7.95 (m, 6 Ar H), 8.52(s, NH). Electrospray Mass Spec: m/z 525.0 (M+H)⁺.

EXAMPLE 12 Benzo[b]thiophene-2-carboxylic Acid(2-{4-[(2-hydroxycarbamoyl-6-methyl-phenyl)-methyl-sulfamoyl]-phenoxy}-ethyl)-amide

[0138] The product of Example 11 (0.2 g, 0.38 mmol) was converted to thehydroxamic acid using the procedure of Example 4 to provide 0.048 g (25%yield) of a white solid. MP 169-171 C ¹H NMR (DMSO-d₆): δ 1.35-1.62 (m,CH2), 1.9 (s, CH3), 3.20 (s, CH3), 3.46-3.51 (m, CH2, CH2), 7.0-7.95 (m,11 Ar H), 8.0 (s, 1 Ar H), 8.58 (t, NH), 9.0 (br s, NH), 10.9 (s, OH).Electrospray Mass Spec: m/z 540.2 (M+H)⁺.

EXAMPLE 132-[[(4-{3-[(1,3-Benzodioxol-5-ylcarbonyl)amino]propoxy}phenyl)sulfonyl](methyl)amino]-3-methylBenzoic Acid

[0139] The product of Example 2 (0.30 g, 0.92 mmol) was coupled toN-(3-hydroxypropyl)-1,3-benzodioxole-5-carboxamide, prepared accordingto Example 20, (0.205 g, 0.92 mmol) using the procedure of Example 3 toprovide 0.23 g (49% yield) of yellow solid. MP 120° C.; ¹H NMR(DMSO-d₆): δ 1.63 (m, CH2) 1.9 (s, CH3), 3.20 (s, CH3), 3.6 (m, CH2),4.1 (m, CH2), 6.07 (s, CH2), 6.9-7.1 (m, 5 Ar H), 7.3-7.5 (m, 3 Ar H),7.88-7.94 (m, 2 Ar H), 8.52 (br s, NH). Electrospray Mass Spec: m/z527.2 (M+H)⁺.

EXAMPLE 14N-{3-[4-({2-[(Hydroxyamino)carbonyl]-6-dimethylanilino}sulfonyl)phenoxy]propyl}-1,3-benzodioxole-5-carboxamide

[0140] The product of Example 13 (0.2 g, 0.38 mmol) was converted to thehydroxamic acid using the procedure of Example 4 to provide 0.102 g (50%yield) of a white solid. MP 102-112° C.; ¹H NMR (DMSO-d₆): δ 1.63 (m,CH2) 1.9 (s, CH3), 3.20 (s, CH3), 3.6 (m, CH2), 4.1 (m, CH2), 6.08 (s,CH2), 6.96-6.99 (m, Ar H), 7.02-7.09 (m, 3 Ar H), 7.30-7.45 (, 3 Ar H),7.52-7.58 (m, 2 Ar H), 7.69-7.72 (d,d, 1 Ar H), 7.82-7.85 (d, 1 Ar H),8.25 (m, NH), 8.40 (br s, NH), 10.9 (br s, OH). Electrospray Mass Spec:m/z 542.1 (M+H)⁺.

EXAMPLE 152-[[(4-{4-[(1,3-Benzodioxol-5-ylcarbonyl)amino]butoxy}phenyl)sulfonyl](methyl)amino]-3-methylBenzoic Acid

[0141] The product of Example 2 (0.30 g, 0.92 mmol) was coupled toN-(4-hydroxybutyl)-1,3-benzodioxole-5-carboxamide, prepared according toExample 21, (0.23 g, 0.96 mmol) using the procedure of Example 3 toprovide 0.30 g (60% yield) of yellow solid. MP 110° C.; ¹H NMR(DMSO-d₆): δ 1.66-1.80 (m,CH2, CH2)1.89 (s, CH3), 3.1 (s, CH3),3.39-3.45 (m, CH2), 4.08 (t, CH2), 6.08 (s, CH2), 6.9 (d, 1 Ar H),7.04-7.08 (m, 2 Ar H), 7.33-7.45 (m, 5 Ar H), 7.53-7.58 (m, 2 Ar H),8.39 (t, NH), 12.8 (s, OH). Electrospray Mass Spec: m/z 541.2 (M+H)⁺.

EXAMPLE 16N-{4-[4-(12-[(Hydroxyamino)carbonyl]-6-dimethylanilino]sulfonyl)phenoxy]butyl}-1,3-benzodioxole-5-carboxamide

[0142] The product of Example 15 (0.15 g, 0.28 mmol) was converted tothe hydroxamic acid using the procedure of Example 4 to provide 0.092 g(40% yield) of a white solid. MP 117-121° C.; ¹H NMR (DMSO-d₆): δ1.66-1.80 (m, CH2, CH2) 1.89 (s, CH3), 3.1 (s, CH3), 3.39-3.45 (m, CH2),4.08 (t, CH2), 6.08 (s, CH2), 6.96 (d, 1 Ar H), 7.04-7.08 (d,d 2 Ar H),7.17-7.19 (d,d 1 Ar H), 7.28-7.38 (m, 3 Ar H), 7.45 (d,d 1 Ar H),7.68-7.80 (m, 2 Ar H), 7.95 (s, 1 Ar H), 8.32 (t, NH), 8.88 (br s, NH),11.0 (s, OH). Electrospray Mass Spec: m/z 540.2 (M+H)⁺.

EXAMPLE 17 N-(4-Hydroxybutyl)-1-benzofuran-2-carboxamide

[0143] 2-Benzofurancarboxylic acid (5.0 g, 30.8 mmol) and4-amino-1-butanol (3.4 ml, 37 mmol) were dissolved in DMF (45 ml).1-hydroxybenzotriazole (5.0 g, 37 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.7 g, 40mmol), and diisopropylethylamine (10.7 ml, 61.7 mmol) were addedsequentially to the solution and allowed to stir at room temperatureovernight. After removing excess solvent in vacuo, the residue was takenup in water and the product was extracted into dichloromethane. Theorganics were combined, washed with brine, dried over Na₂SO₄, andsolvent removed in vacuo to give a solid which was purified by columnchromatography (100% ethyl acetate) to give 3.5 g (50% yield) of a whitesolid. ¹H NMR (DMSO-d₆): δ 1.35-1.62 (m, CH2, CH2), 3.29 (q, CH2), 3.41(q, CH2), 4.3 (t, NH), 7.78 (d, 1 Ar H), 7.63 (d, 1 Ar H), 7.51 (s, 1 ArH), 7.46 (t, 1 Ar H), 7.35 (t, 1 Ar H), 8.71 (t, NH) Electrospray MassSpec: m/z 234.2 (M+H)⁺.

EXAMPLE 18 N-(3-Hydroxypropyl)-1H-indole-2-carboxamide

[0144] 1H Indole-2-carboxylic acid (5.0 g, 31 mmol) and3-amino-1-propanol (2.2 ml, 40.3 mmol) were coupled according to theprocedure of Example 17 to 5.46 g (80% yield) of an off-white solid. MP152-156° C.; ¹H NMR (DMSO-d₆): δ 1.6-1.7 (m, CH2), 3.31-3.37 (q, CH2),3.41-3.51 (q, CH2), 4.52 (t, NH), 7.0-7.19 (m, 3 Ar H), 7.40 (d, 1 ArH), 7.58 (d, 1 Ar H), 8.46 (t, NH), 11.9 (s, NH) Electrospray Mass Spec:m/z217.2 (M+H)⁺.

EXAMPLE 19 N-(2-Hydroxyethyl)-1-benzothiophene-2-carboxamide

[0145] 2-Benzothiophenecarboxylic acid (3.0 g, 16.8 mmol) andethanolamine (1.21 ml, 20 mmol) were coupled according to the procedureof Example 17 to 2.7 g (73% yield) of an off-white solid. ¹H NMR(DMSO-d₆): δ 3.3 (m, CH2), 3.5 (q, CH2), 4.79 (t, NH), 7.1-7.4 (m, 2 ArH), 7.90 (m, 1 Ar H), 7.95 (m, 1 Ar H), 8.09 (s, 1 Ar H), 8.89 (t, NH)Electrospray Mass Spec: m/z 222.2 (M+H)⁺.

EXAMPLE 20 N-(3-Hydroxyproyl)-1,3-benzodioxole-5-carboxamide

[0146] 1,3-Benzodioxole -5-carboxylic acid (2.0 g, 12.0 mmol) and3-amino-1-propanol (0.8 ml, 15.6 mmol) were coupled according to theprocedure of Example 17 to 1.74 g (65% yield) of a white solid. MP112-113° C.; ¹H NMR (DMSO-d₆): δ 1.65 (m, CH2), 3.27 (m, CH2), 3.42 (m,CH2), 4.45 (t, NH), 6.0 (s, CH2), 6.98 (d, 1 Ar H), 7.37 (d, 1 Ar H),7.4 (d-d, 1 Ar H), 8.28 (t, NH) Electrospray Mass Spec: m/z 224.2(M+H)⁺.

EXAMPLE 21 N-(4-Hydroxybutyl)-1,3-benzodioxole-5-carboxamide

[0147] 1,3-Benzodioxole -5-carboxylic acid (2.0 g, 12.0 mmol) and4-amino-1-butanol (1.4 ml, 15.6 mmol) were coupled according to theprocedure of Example 17 to 2.1 g (75% yield) of a pale yellow solid. MP95-98° C.; ¹H NMR (DMSO-d₆): δ 1.38-1.65 (m, CH2, CH2), 3.31 (q, CH2),3.39 (q, CH2), 4.39 (t, NH), 6.08 (s, CH2), 6.98 (d, 1 Ar H), 7.37 (d, 1Ar H), 7.4 (d-d, 1 Ar H), 8.27 (t, NH) Electrospray Mass Spec: m/z 238.2(M+H)⁺.

EXAMPLE 22 N-(2-Hydroxyethyl) 2-quinolinecarboxamide

[0148] To a solution of quinaldic acid (5.0 g, 28.87 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.5 g,28.87 mmol), and 1-hydroxybenzotriazole (5.1 g, 37.49 mmol) in DMF (60mL) at 0° C. was added ethanolamine (1.74 mL, 28.87 mmol) and4-methylmorpholine (4.76 mL, 43.31 mmol). The reaction was stirred at 0°C. for an additional 10 minutes and then warmed to room temperature andstirred for 2 hours. The reaction mixture was then diluted with ethylacetate, washed 3 times with H₂O, once with NaHCO₃ (sat), once withbrine, dried over MgSO₄, and concentrated in vacuo to provide 1.5 g (24%yield) of a pale yellow solid. Electrospray Mass Spec: m/z 216.8 (M+H)⁺.

EXAMPLE 23 N-(3-Hydroxypropyl)-1-benzofuran-2-carboxamide

[0149] 2-Benzofurancarboxylic acid (5.0 g, 30.8 mmol) and3-amino-1-propanol (2.83 ml, 37 mmol) were coupled according to theprocedure of example 22 to provide 1.39 g (17.2% yield) of the desiredproduct as a yellow solid. Electrospray Mass Spec: m/z219.8 (M+H)⁺.

EXAMPLE 24 N-(3-Hydroxypropyl)-1-benzothiophene-2-carboxamide

[0150] 2-Benzothiophenecarboxylic acid (5.0 g, 28.05 mmol) and3-amino-1-propanol (2.57 ml, 33.66 mmol) were coupled according to theprocedure of Example 22 to provide 3.45 g (52.3% yield) of the desiredproduct as an orange solid. Electrospray Mass Spec: m/z 235.9 (M+H)⁺.

EXAMPLE 25 N-(2-Hydroxypropyl)-1-benzofuran-2-carboxamide

[0151] 2-Benzofurancarboxylic acid (1.0 g, 6.16 mmol) and ethanolamine(0.37 ml, 6.16 mmol) were coupled according to the procedure of Example22 to provide 0.55 g (43% yield) of the desired product as a yellowsolid. MP 90-91° C. Electrospray Mass Spec: m/z 205.8 (M+H)⁺.

EXAMPLE 262-[[(4-{3-[(1-Benzothiophene-2-ylcarbonyl)amino]propoxy}phenyl)sulfonyl](methyl)amino]-3-methylBenzoic Acid

[0152] The product of Example 2 (0.5 g, 1.58 mmol) was coupled toN-(3-hydroxypropyl)-1-benzothiophene-2-carboxamide (1.26 g, 5.37 mmol)using the procedure of Example 3 to provide 0.16 g (19% yield) of an offwhite solid. Electrospray Mass Spec: m/z 539.3 (M+H)⁺.

EXAMPLE 27N-{3-{4-({2-[(Hydroxyamino)carbonyl]-6-dimethylanilino}-sulfonyl)phenoxy]propyl}-1-benzothiophene-2-carboxamide

[0153] The product of Example 26 (0.16 g, 0.30 mmol) was converted tothe hydroxamic acid using the procedure of Example 4 to provide 0.1 g(60% yield) as a pink foam. MP 100-105° C. Electrospray Mass Spec: m/z554.0 (M+H)⁺.

EXAMPLE 28 2-(4-Fluoro-benzenesulfonylamino)-3,5-dimethyl-benzoic acidMethyl Ester

[0154] To a solution of 2.00 g (0.011 mmol) of methyl3,5-dimethylanthranilic acid in 10.0 mL of pyridine was added 2.17(0.011 mmol) of 4-fluorobenzenesulfonyl chloride. The reaction mixturewas stirred for 24 h at room temperature and then diluted withchloroform and washed with 5% HCl solution and water. The organic layerwas then dried over MgSO₄, filtered and concentrated in vacuo. Theresidue was triturated with ether-hexanes and the resulting solid wasfiltered and dried to provide 3.09 g (82%) of the desired product as awhite solid. Electrospray Mass Spec: m/z 338.3 (M+H)⁺.

EXAMPLE 292-[Benzyl-(4-fluoro-benzenesulfonyl)-amino]-3,5-dimethyl-benzoic AcidMethyl Ester

[0155] To a solution of 1.00 g (2.86 mmol) of the product of Example 28in 10 mL of DMF was added 0.14 g (3.57 mmol) of 60% sodium hydride. Theresulting mixture was stirred for 30 min at room temperature and then0.42 mL (3.57 mmol) of benzyl bromide was added. This reaction mixturewas stirred overnight at room temperature, poured into water and thenextracted with ether. The combined organics were washed with water andbrine, dried over MgSO₄, filtered and concentrated in vacuo to provide awhite solid which was recrystallized from ethyl acetate (EtOAc)/Hexanesto provide 1.084 g (85%) of the desired product as a white solid.Electrospray Mass Spec: m/z 428.3 (M+H)⁺.

EXAMPLE 302-[[(4-{2-[(Benzofuran-2-carbonyl)-amino]ethoxy}benzenesulfonyl]benzylamino]-3,5-dimethyl-benzoicAcid

[0156] Sodium hydride (0.240 g, 5.99 mmol, 60% dispersion in mineraloil) was added to DMF (8 ml) and cooled to 0° C. A solution ofN-(2-hydroxypropyl)-1-benzofuran-2-carboxamide (0.6 g, 2.92 mmol) in DMF(1.5 ml) was added and allowed to stir for 10 min at 0° C. and then for15 min at rt. The product of Example 29 (0.383 g, 0.87 mmol) was thenadded in one portion and the reaction was allowed to stir overnight. Thereaction was then quenched with water, extracted with EtOAc, washed withwater, brine, dried over MgSO₄, and concentrated in vacuo to provide anoil which was chromatographed using hexane to 2/1 hexane/EtOAc as eluantto provide the product as a mixture of esters which was used directly inthe next reaction. The mixture of esters (233 mg) was dissolved inTHF:MeOH:H₂O (1.2 mL:0.7 mL:1.2 mL) and LiOH (13.7 mg, 0.32 mmol) wasadded. The reaction was heated at reflux overnight. The reaction wascooled to rt, quenched with 6M HCl and extracted with CH₂Cl₂. Theorganics were washed with brine, dried over Na₂SO₄, concentrated invacuo to provide an oil which was chromatographed using hexane to 9/1CH₂Cl₂/MeOH as eluant to provide 80 mg (44% yield) of the product acid.Electrospray Mass Spec: m/z 597.2 (M−H)⁻.

EXAMPLE 31 Benzofuran-2-carboxylic acid(2-{4-[benzyl-(2-hydroxycarbamoyl-4,6-dimethyl-phenyl)-sulfamoyl]-phenoxy}-ethyl)-amide

[0157] DMF (0.0021 mL, 0.26 mmol) was added to oxallyl chloride (0.13ml, 0.267 mmol, 2M in CH₂Cl₂) at 0° C. This mixture was allowed to warmto rt and stir for 45 min. To this suspension was added a solution ofthe product from Example 30 (80 mg, 0.13 mmol) in DMF (1 mL). Thesolution of the acid chloride was then stirred for 4 hours.

[0158] In a separate flask, 0.27 mL (1.95 mmol) of triethylamine wasadded to 0° C. mixture of 0.09 g (1.3 mmol) of hydroxylaminehydrochloride in 1.49 mL of THF and 0.43 mL of water. After this mixturehad stirred for 15 min at 0° C., the acid chloride solution was added toit in one portion and the resulting solution was allowed to warm to roomtemperature with stirring overnight. The reaction mixture was thenacidified to pH 3 with 10% HCl and extracted with EtOAc. The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated invacuo. The crude residue was chroamtographed using 95/5 CH₂Cl₂/MeOH aseluant to provide 0.020 g (25%) of the desired hydroxamic acid as awhite solid. Electrospray Mass Spec: m/z 612.2 (M-H)-.

Pharmacology Procedures for Measuring MMP-1, MMP-9, and MMP-13Inhibition

[0159] These assays are based on the cleavage of a thiopeptidesubstrates such asAc-Pro-Leu-Gly(2-mercapto-4-methyl-pentanoyl)-Leu-Gly-OEt by the matrixmetalloproteinases MMP-1, MMP-13 (collagenases) or MMP-9 (gelatinase),which results in the release of a substrate product that reactscolorimetrically with DTNB (5,5′-dithiobis(2-nitro-benzoic acid)). Theenzyme activity is measured by the rate of the color increase. Thethiopeptide substrate is made up fresh as a 20 mM stock in 100% DMSO andthe DTNB is dissolved in 100% DMSO as a 100 mM stock and stored in thedark at room temperature. Both the substrate and DTNB are dilutedtogether to 1 mM with substrate buffer (50 mM HEPES pH 7.5, 5 mM CaCl₂)before use. The stock of enzyme is diluted with assay buffer (50 mMHEPES, pH 7.5, 5 mM CaCl₂, 0.02% Brij) to the desired finalconcentration. The assay buffer, enzyme, vehicle or inhibitor, andDTNB/substrate are added in this order to a 96 well plate (totalreaction volume of 200 μl) and the increase in color is monitoredspectrophotometrically for 5 minutes at 405 nm on a plate reader and theincrease in color over time is plotted as a linear line.

[0160] Alternatively, a fluorescent peptide substrate is used. In thisassay, the peptide substrate contains a fluorescent group and aquenching group. Upon cleavage of the substrate by an MMP, thefluorescence that is generated is quantitated on the fluorescence platereader. The assay is run in HCBC assay buffer (50 mM HEPES, pH 7.0, 5 mMCa⁺², 0.02% Brij, 0.5% Cysteine), with human recombinant MMP-1, MMP-9,or MMP-13. The substrate is dissolved in methanol and stored frozen in 1mM aliquots. For the assay, substrate and enzymes are diluted in HCBCbuffer to the desired concentrations. Compounds are added to the 96 wellplate containing enzyme and the reaction is started by the addition ofsubstrate. The reaction is read (excitation 340 nm, emission 444 nm) for10 min. and the increase in fluorescence over time is plotted as alinear line.

[0161] For either the thiopeptide or fluorescent peptide assays, theslope of the line is calculated and represents the reaction rate. Thelinearity of the reaction rate is confirmed (r²>0.85). The mean (x±sem)of the control rate is calculated and compared for statisticalsignificance (p<0.05) with drug-treated rates using Dunnett's multiplecomparison test. Dose-response relationships can be generated usingmultiple doses of drug and IC₅₀ values with 95% CI are estimated usinglinear regression.

Procedure for Measuring TACE Inhibition

[0162] Using 96-well black microtiter plates, each well receives asolution composed of 10 μL tumor necrosis factor-alpa converting enzyme(TACE; Immunex, final concentration 1 μg/mL), 70 μL Tris buffer, pH 7.4containing 10% glycerol (final concentration 10 mM), and 10 μL of testcompound solution in DMSO (final concentration 1 μM, DMSO concentration<1%) and incubated for 10 minutes at room temperature. The reaction isinitiated by addition of a fluorescent peptidyl substrate (finalconcentration 100 μM) to each well and then shaking on a shaker for 5sec.

[0163] The reaction is read (excitation 340 nm, emission 420 nm) for 10min. and the increase in fluorescence over time is plotted as a linearline. The slope of the line is calculated and represents the reactionrate.

[0164] The linearity of the reaction rate is confirmed (r²>0.85). Themean (x±sem) of the control rate is calculated and compared forstatistical significance (p<0.05) with drug-treated rates usingDunnett's multiple comparison test. Dose-response relationships can begenerate using multiple doses of drug and IC₅₀ values with 95% CI areestimated using linear regression.

[0165] Results of the above in-vitro matrix metalloproteinase inhibitionand TACE inhibition pharmacological assays are given in Table I below.

[0166] Biological Data: Exampl MMP-1^(a) MMP-9^(a) MMP-13^(a) TACE^(b) 44244 337 73 19.9 6 5450 510 4.9 21.3 8 5122 84 467 43.6 10 5642 305 17835.7 12 >10 μM   914 595 15.2 14 1481 63.6 110 42.1 16 999 55.7 83.527.4 27 30 μM 1390 43 22.0 31 10 μM 945 17.1 18.9

[0167] Compounds of this invention are shown to inhibit the enzymesMMP-1, MMP-9, MMP-13, and TACE and are therefore useful in the treatmentof conditions resulting from overexpression or excess activation of MMPsand TACE. Such diseases are, for example, atherosclerosis,atherosclerotic plaque formation, reduction of coronary thrombosis fromatherosclerotic plaque rupture, restenosis, MMP-mediated osteopenias,inflammatory diseases of the central nervous system, skin aging,angiogenesis, tumor metastasis, tumor growth, osteoarthritis, rheumatoidarthritis, septic arthritis, comeal ulceration, abnormal wound healing,bone disease, proteinuria, aneurysmal aortic disease, degenerativecartilage loss following traumatic joint injury, demyelinating diseasesof the nervous system, cirrhosis of the liver, glomerular disease of thekidney, premature rupture of fetal membranes, inflammatory boweldisease, and periodontal disease. Compounds of the present invention arealso believed to be useful for the treatment of age related maculardegeneration, diabetic retinopathy, proliferative vitreoretinopathy,retinopathy of prematurity, ocular inflammation, keratoconus, Sjogren'ssyndrome, myopia, ocular tumors, ocular angiogenesis/neovascularizationor corneal graft rejection. In addition, compounds of the presentinvention are believed to be useful for the treatment of graftrejection, cachexia, anorexia, inflammation, fever, insulin resistance,septic shock, congestive heart failure, inflammatory disease of thecentral nervous system, or HIV infection.

What is claimed is:
 1. A compound of formula I

where the hydroxamic acid moiety and the sulfonamido moiety are bondedto adjacent carbons of group A wherein: A is aryl, heteroaryl orheteroaryl fused to a phenyl ring; Z is aryl, heteroaryl, or heteroarylfused to a phenyl; E and G are independently CH₂, NR⁵, or O, or S or abond: Y is cycloalkyl, cycloheteroalkyl, —C₁-C₅-perfluoroalkyl, alkyl,alkenyl, alkynyl, heteroalkyl, alkylaryl, or heteroaryl; J is aryl,heteroaryl, heteroaryl fused to a phenyl, cycloalkyl, cycloheteroalkyl,—C₁-C₅-perfluoroalkyl, alkyl, alkenyl, or alkynyl; R⁵ and R⁶ areindependently H, aryl, heteroaryl, cycloalkyl, cycloheteroalkyl,—C₁-C₄-perfluoroalkyl, alkyl, alkenyl, or alkynyl; R⁷ is hydrogen,alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or 3-6 memberedcycloheteroalkyl; or R⁷CH₂—N—A- can form a non-aromatic 1,2-benzo-fused7-10 membered heterocyclic ring optionally containing an additionalheteroatom selected from O, S and N wherein said heterocyclic ring maybe optionally fused to another benzene ring; L is —C(O)—, S(O)_(y),—NR⁵C(O)NR⁶—, —NR⁵C(O)O—, —OC(O)NR⁵—, —SC(O)—, —C(O)S—, —NR⁵C(O)—,—C(O)NR⁵—, —SC(O)NR⁵, —NR⁵C(O)S—, —OC(O)O—; y is 1 or 2; and thepharmaceutically acceptable salts thereof and the optical isomers anddiastereomers thereof.
 2. The compound according to claim 1 wherein A isaryl, heteroaryl or hetcroaryl fused to a phenyl ring optionallysubstituted by R¹, R², R³ and R⁴; Z is aryl, heteroaryl, or heteroarylfused to a phenyl, optionally substituted by R¹⁰, R¹¹, R¹²and R¹³; R¹,R², R³, R⁴, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R²⁰, R²¹, R²², R²³R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R³⁰ and R³¹ are independently —H, —COR⁵,—F, —Br, —Cl, —I, C(O)NR⁵OR⁶, —CN, —OR⁵, —C₁-C₄-perfluoroalkyl,—S(O)_(x)R⁵, —OPO(OR⁵)OR⁶, —PO(OR⁶)R⁵, —OC(O)NR⁵R⁶, —COOR⁵, —CONR⁵R⁶,—SO₃H, —NR⁵R⁶, —NR⁵COR⁶, —NR⁵COOR⁶, —SO₂NR⁵R⁶, —NO₂, —N(R⁵)SO₂R⁶,—NR⁵CONR⁵R⁶NR⁵C(═NR⁶)NR⁵R⁶, 3-6 membered cycloheteroalkyl, aryl,heteroaryl, biphenyl, —SO₂NHCOR¹⁸, —CONHSO₂R¹⁸, tetrazol-5-yl, —SO₂NHCN,—SO₂NHCONR⁵R⁶ or straight chain or branched —C₁-C₆ alkyl,—C₂-C₆-alkenyl, or —C₂-C₆-alkynyl, or —C₃-C₆-cycloalkyl, each optionallysubstituted with —COR⁵, —CN, —C₂-C₆ alkenyl, —C₂-C₆ alkynyl, —OR⁵,—C₁-C₄-perfluoroalkyl, —S(O)_(x)R⁵, —OC(O)NR⁵R⁶, —COOR⁵, —CONR⁵R⁶,—SO₃H, —NR⁵R⁶, —NR⁵COR⁶, —NR⁵COOR⁶, —SO₂NR⁵R⁶, —NO₂, —N(R⁵)SO₂R⁶,—NR⁵CONR⁵R⁶, —C₃-C₆cycloalkyl, 3-6 membered cycloheteroalkyl, aryl,heteroaryl, biphenyl, —SO₂NHCOR¹⁸, —CONHSO₂R¹⁸; —PO(OR⁵)OR⁶, —PO(OR⁶)R⁵,-tetrazol-5-yl, C(O)NR⁵OR⁶, —NR⁵C(═NR⁶)NR⁵R⁶, —SO₂NHCONR⁵R⁶ or —SO₂NHCN;or when any of R¹ and R² or R¹⁰ and R¹¹ or R¹⁴ and R¹⁵ are on adjacentcarbons of A or J or Z respectively, then each pair of R¹ and R² or R¹⁰and R¹¹ or R¹⁴ and R¹⁵ together with the carbons to which they areattached can form a 5 to 7 membered saturated or unsaturatedheterocyclic ring, a 5-6 membered heteroaryl ring, or a 5 to 7 memberedsaturated or unsaturated carbocyclic ring; x is 0-2; E and G areindependently CH₂, NR⁵, or O, or S or a bond: Y is —C₃-C₆-cycloalkyl,—C₃-C₆-cycloheteroalkyl, —C₁-C₅-perfluoroalkyl, straight chain orbranched —C₁-C₆ alkyl, straight or branched chain —C₂-C₆-alkenyl, orstraight or branched chain C₂-C₆-alkynyl or heteroalkyl, alkylaryl,heteroaryl optionally substituted with R²⁰, R²¹, R²², and R²³; J isaryl, heteroaryl, or heteroaryl fused to a phenyl; optionallysubstituted with R¹⁴, R¹⁵, R¹⁶, and R¹⁷ or —C₃-C₆-cycloalkyl,—C₃-C₆-cycloheteroalkyl, —C₁-C₅-perfluoroalkyl, straight chain orbranched —C₁-C₆ alkyl, straight or branched chain C₂-C₆-alkenyl, orstraight or branched chain C₂-C₆-alkynyl; R⁵ and R⁶ are independently H,aryl, heteroaryl, —C₃-C₆-cycloalkyl, —C₃-C₆-cycloheteroalkyl,—C₁-C₄-perfluoroalkyl, or straight chain or branched —C₁-C₆ alkyl,—C₂-C₆-alkenyl, or —C₂-C₆-alkynyl, each optionally substituted with —OH,—COR⁸, —CN, —C(O)NR⁸OR⁹, —C₂-C₆-alkenyl, —C₂-C₆-alkynyl, —OR⁸,—C₁-C₄-perfluoroalkyl, —S(O)_(x)R⁸, —OPO(OR⁸)OR⁹, —PO(OR⁸)R⁹,—OC(O)NR⁸R⁹, —COOR⁸, —CONR⁸R⁹, —SO₃H, —NR⁸R⁹, —NCOR⁸R⁹, —NR⁸COOR⁹,—SO₂NR⁸R⁹, —NO₂, —N(R⁸)SO₂R⁹, —NR⁸CONR⁸R⁹, —C₃-C₆ cycloalkyl, 3-6membered cycloheteroalkyl, aryl, heteroaryl, —SO₂NHCOR⁹, —CONHSO₂R¹⁹,-tetrazol-5-yl, NR⁸C(═NR⁹)NR⁸R⁹, —SO₂NHCONR⁸R⁹, or —SO₂NHCN; R⁷ ishydrogen, straight chain or branched —C₁-C₆-alkyl, —C₂-C₆-alkenyl, or—C₂-C₆-alkynyl each optionally substituted with —OH, —COR⁵, —CN,—C₂-C₆-alkenyl, 15-C₂-C₆-alkynyl, —OR⁵, —C₁-C₄-perfluoroalkyl,—S(O)_(x)R⁵, OPO(OR⁵)OR⁶, —PO(OR⁵)R⁶, —OC(O)NR⁵R⁶, —COOR⁵, —CONR⁵R⁶,—SO₃H, —NR⁵R⁶, —NR⁵COR⁶, —NR⁵COOR⁶, —SO₂NR⁵R⁶, —NO₂, —N(R⁵)SO₂R⁶,—NR⁵CONR⁵R⁶, —C₃-C₆ cycloalkyl, —C₃-C₆-cycloheteroalkyl, -aryl,heteroaryl, —SO₂NHCOR³², —CONHSO₂R³², -tetrazol-5-yl, —NR⁵C(═NR6)NR⁵R⁶,—C(O)N R⁵OR⁶, —SO₂NHCONR⁵R⁶ or SO₂NHCN; or R⁷ is phenyl or naphthyl,optionally substituted by R²⁴, R²⁵, R²⁶ and R²⁷ or a 5 to 6 memberedheteroaryl group optionally substituted by R²⁸, R²⁹, R³⁰ and R³¹; or R⁷is C₃-C₆ cycloalkyl or 3-6 membered cycloheteroalkyl; or R⁷CH₂—N—A- canform a non-aromatic 1,2-benzo-fused 7-10 membered heterocyclic ringoptionally containing an additional heteroatom selected from O, S and Nwherein said heterocyclic ring may be optionally fused to anotherbenzene ring; R⁸ and R⁹ are independently H, aryl or heteroaryl, —C₃-C₇cycloalkyl or 3 to 6 membered cycloheteroalkyl, —C₁-C₄-perfluoroalkyl,straight chain or branched —C₁-C₆-alkyl, —C₂-C₆-alkenyl, or—C₂-C₆-alkynyl, each optionally substituted with hydroxy, alkoxy,aryloxy, —C₁-C₄-perfluoroalkyl, amino, mono- and di-C₁-C₆-alkylamino,carboxylic acid, carboalkoxy and carboaryloxy, nitro, cyano, carboxamidoprimary, mono- and di-C₁-C₆-alkylcarbamoyl; R¹⁸ and R³² areindependently aryl, heteroaryl, —C₃-C₆-cycloalkyl,—C₃-C₆-cycloheteroalkyl, —C₁-C₄-perfluoroalkyl, or straight chain orbranched —C₁-C₆ alkyl, —C₂-C₆-alkenyl, or —C₂-C₆-alkynyl, eachoptionally substituted with —OH, —COR⁸, —CN, —C(O)NR⁸OR⁹,—C₂-C₆-alkenyl, —C₂-C₆-alkynyl, —OR⁸, —C₁-C₄-perfluoroalkyl,—S(O)_(x)R⁸, —OPO(OR⁸)OR⁹, —PO(OR⁸)R⁹, —OC(O)NR⁸R⁹, —COOR⁸, —CONR⁸R⁹,—SO₃H, —NR⁸R⁹, —NCOR⁸R⁹, —NR⁸COOR⁹, —SO₂NR⁸R⁹, —NO₂, —N(R⁸)SO₂R⁹,NR⁸CONR⁸R⁹, —C₃-C₆ cycloalkyl, 3-6 membered cycloheteroalkyl, aryl,heteroaryl, —SO₂NHCOR¹⁹, —CONHSO₂R¹⁹, -tetrazol-5-yl, NR⁸C(═NR⁹)NR⁸R⁹,—SO₂NHCONR⁸R⁹, or —SO₂NHCN; R¹⁹ is aryl or heteroaryl, —C₃-C₇cycloalkylor 3 to 6 membered cycloheteroalkyl, —C₁-C₄-perfluoroalkyl, straightchain or branched —C₁-C₆-alkyl, —C₂-C₆-alkenyl, or —C₂-C₆-alkynyl, eachoptionally substituted with hydroxy, alkoxy, aryloxy,—C₁-C₄-perfluoroalkyl, amino, mono- and di-C₁-C₆-alkylamino, carboxylicacid, carboalkoxy and carboaryloxy, nitro, cyano, carboxamido primary,mono- and di-C₁-C₆-alkylcarbamoyl; L is —C(O)—, S(O)_(y), —NR⁵C(O)NR⁶—,—NR⁵C(O)O—, —OC(O)NR⁵—, —SC(O)—, —C(O)S—, —NR⁵C(O)—, —C(O)NR⁵—,—SC(O)NR⁵, —NR⁵C(O)S—, —OC(O)O—; y is 1 or 2; and the pharmaceuticallyacceptable salts thereof and the optical isomers and diastereomersthereof.
 3. The compound according to claim 1 wherein E and G areindependently selected from NH, O and S.
 4. The compound according toclaim 3 wherein E is O and G is NH.
 5. The compound according to claim 1wherein J is aryl or heteroaryl fused to a phenyl.
 6. The compoundaccording to claim 5 wherein J is quinolyl, benzothienyl, benzofuranyl,benzodioxolyl or indolyl optionally substituted by one or mor of R¹⁴,R¹⁵, R⁶and R¹⁷.
 7. The compound according to claim 5 wherein J isselected from benzofuranyl, benzothienyl, quinolyl, benzodioxolyl orindolyl.
 8. The compound according to claim 5 wherein J is selected fromquinol-2-yl, benzo[b]thiophen-2-yl, benzofuran-2-yl, indol-2-yl or1,3-benzodioxol-2-yl.
 9. The compound according to claim 1 wherein A isphenyl optionally substituted by H or straight or branched chain C₁-C₆alkyl.
 10. The compound according to claim 1 wherein Y is C₁-C₆ straightchain alkyl.
 11. The compound according to claim 10 wherein Y is C₂-C₃straight chain alkyl.
 12. The compound of claim 1 wherein E and G areCH₂ and Y is straight chain or branched —C₁-C₆ alkyl.
 13. The compoundaccording to claim 1 wherein G is CH₂ and Y is C₂-C₅-perfluoroalkyl, orstraight chain or branched —C₁-C₆ alkyl.
 14. The compound according toclaim 1 wherein Z is phenyl.
 15. The compound according to claim 1wherein R⁷ is H, straight or branched chain C₁-C₆ alkyl or phenyl 16.The compound according to claim 1 wherein L is —CO—.
 17. The compoundaccording to claim 1 which is selected from the following:Quinoline-2-carboxylic acid(2-{4-[(2-hydroxycarbamoyl-6-methyl-phenyl)-methyl-sulfamoyl]-phenoxy}-ethyl)-amide;Benzofuran-2-carboxylic acid(3-{4-[(2-hydroxycarbamoyl-6-methyl-phenyl)-methyl-sulfamoyl]-phenoxy}-propyl)-amide;Benzofuran-2-carboxylic acid(4-{4-[(2-hydroxycarbamoyl-6-methyl-phenyl)-methyl-sulfamoyl]-phenoxy}-butyl)-amide;1H-Indole-2-carboxylic acid (3-{4-[(2-hydroxycarbamoyl-6-methyl-phenyl)-methyl-sulfamoyl]-phenoxy}-propyl)-amide;Benzo[b]thiophene-2-carboxylic acid(2-{4-[(2-hydroxycarbamoyl-6-methyl-phenyl)-methyl-sulfamoyl]-phenoxy}-ethyl)-amide;N-{3-[4-({2-[(Hydroxyamino)carbonyl]-6-dimethylanilino}sulfonyl)-phenoxy]propyl}-1,3-benzodioxole-5-carboxamide;N-{4-[4-({2-[(Hydroxyamino)carbonyl]-6-dimethylanilino}sulfonyl)-phenoxy]butyl}-1,3-benzodioxole-5-carboxamide;N-{3-[4-({2-[(Hydroxyamino)carbonyl]-6-dimethylanilino}-sulfonyl)-phenoxy]propyl}-1-benzothiophene-2-carboxamide;and Benzofuran-2-carboxylic acid(2-{4-[benzyl-(2-hydroxycarbamoyl-4,6-dimethyl-phenyl)-sulfamoyl]-phenoxy}-ethyl)-amide.18. A method of treating a pathological condition or disorder mediatedby matrix metalloproteinases in mammals which comprises providing to amammal in need thereof a therapeutically effective amount of a matrixmetalloproteinase inhibiting compound according to claim
 1. 19. Themethod according to claim 18 wherein E and G are independently selectedfrom NH, O and S.
 20. The method according to claim 19 wherein E is Oand G is NH.
 21. The method according to claim 18 wherein J is aryl orheteroaryl fused to a phenyl.
 22. The method according to claim 21wherein J is aryl.
 23. The method according to claim 18 wherein A isphenyl optionally substituted by H or straight or branched chain C₁-C₆alkyl.
 24. The method according to claim 18 wherein Y is C₁-C₆ straightchain alkyl.
 25. The method according to claim 18 wherein E and G areCH₂ and Y is straight chain or branched —C₁-C₆ alkyl.
 26. The methodaccording to claim 18 wherein G is CH₂ and Y is C₂-C₅-perfluoroalkyl, orstraight chain or branched —C₁-C₆ alkyl.
 27. The method according toclaim 18 wherein Z is phenyl.
 28. The method according to claim 18wherein R⁷ is H, straight or branched chain C₁-C₆ alkyl or phenyl 29.The method according to claim 18 wherein L is —CO—.
 30. A method oftreating a patient suffering from a condition selected fromatherosclerosis, atherosclerotic plaque formation, reduction of coronarythrombosis from atherosclerotic plaque rupture, restenosis, MMP-mediatedosteopenias, inflammatory diseases of the central nervous system, skinaging, angiogenesis, tumor metastasis, tumor growth, osteoarthritis,rheumatoid arthritis, septic arthritis, corneal ulceration, abnormalwound healing, bone disease, proteinuria, aneurysmal aortic disease,degenerative cartilage loss following traumatic joint injury,demyelinating diseases of the nervous system, cirrhosis of the liver,glomerular disease of the kidney, premature rupture of fetal membranes,inflammatory bowel disease, or periodontal disease which comprisesproviding a therapeutically effective amount of a compound defined inclaim
 1. 31. A method of treating a patient suffering from a conditionselected from age related macular degeneration, diabetic retinopathy,proliferative vitreoretinopathy, retinopathy of prematurity, ocularinflammation, keratoconus, Sjogren's syndrome, myopia, ocular tumors,ocular angiogenesis/neovascularization or corneal graft rejection whichcomprises providing a therapeutically effective amount of a compounddefined in claim
 1. 32. A method of treating a patient suffering from acondition selected from rheumatoid arthritis, graft rejection, cachexia,anorexia, inflammation, fever, insulin resistance, septic shock,congestive heart failure, inflammatory disease of the central nervoussystem, or HIV infection which comprises providing a therapeuticallyeffective amount of a compound as defined in claim
 1. 33. Apharmaceutical composition comprising a pharmaceutical carrier and atherapeutically effective amount of a matrix metalloproteinaseinhibiting compound defined in claim
 1. 34. A process for preparing acompound of formula (I) as defined in claim 1 which comprises one of thefollowing: a) reacting a compound of formula II:

 wherein J, L, G, Y, E, Z, A and R⁷ are defined in claim 1 or a reactivederivative thereof, with a compound of formula III: NH₂OH  (III) to givea corresponding compound of formula I; b) resolving a mixture (e.g.racemate) of optically active isomers of a compound of formula I toisolate one enantiomer or diastereomer substantially free of the otherenantiomer or diastereomers; c) acidifying a basic compound of formula Iwith a pharmaceutically acceptable acid to give a pharmaceuticallyacceptable salt.
 35. A process for the preparation of compound offormula I

where the hydroxamic acid moiety and the sulfonamido moiety are bondedto adjacent carbons of group A wherein: A is aryl, heteroaryl orheteroaryl fused to a phenyl ring; Z is aryl, heteroaryl, or heteroarylfused to a phenyl; E and G are independently CH₂, NR⁵, or O, or S or abond: Y is cycloalkyl, cycloheteroalkyl, —C₁-C₅-perfluoroalkyl, alkyl,alkenyl, alkynyl, heteroalkyl, alkylaryl, or heteroaryl; J is aryl,heteroaryl, heteroaryl fused to a phenyl, cycloalkyl, cycloheteroalkyl,—C₁-C₅-perfluoroalkyl, alkyl, alkenyl, or alkynyl; R⁵ and R⁶ areindependently H, aryl, heteroaryl, cycloalkyl, cycloheteroalkyl,—C₁-C₄-perfluoroalkyl, alkyl, alkenyl, or alkynyl; R⁷ is hydrogen,alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or 3-6 memberedcycloheteroalkyl; or R⁷CH₂—N-A- can form a non-aromatic 1,2-benzo-fused7-10 membered heterocyclic ring optionally containing an additionalheteroatom selected from O, S and N wherein said heterocyclic ring maybe optionally fused to another benzene ring; L is —C(O)—, S(O)_(y),—NR⁵C(O)NR⁶—, —NR⁵C(O)O—, —OC(O)NR⁵—, —SC(O)—, —C(O)S—, —NR⁵C(O)—,—C(O)NR⁵—, —SC(O)NR⁵, —NR⁵C(O)S—, —OC(O)O—; y is 1 or 2; and thepharmaceutically acceptable salts thereof and the optical isomers anddiastereomers thereof; which process comprises reacting NH₂-A-CO₂CH₃wherein A is as previously defined with F-Z-SO₂Cl wherein Z is aspreviously defined to form a first intermediate

alkylating said first intermediate to form a second intermediate

wherein R⁷ is as previously defined; said second intermediate being a)hydrolyzed to form the carboxylic acid and then subjected tonucleophilic displacement or b) treated directly with a suitablenucleophile and then hydrolyzed to the carboxylic acid to for a thirdintermediate

wherein J, L, G, Y, and E are as previously defined; and converting saidthird intermediate to the corresponding hydroxamic acid to form thecompound of formula I.